Investigation of changes in neurotrophic factor and serum neuroactive steroidlevels after repetitive transcranial magnetic stimulation (rTMS) treatment inmajor depressive disorder patients

Introduction: rTMS is a somatic treatment method with proven therapeutic efficacy in major depressive disorder. There are hypotheses that it acts on neuroendocrinological, neurotrophic, immunological and neurotransmitter systems. It has been shown that there are changes in neuroactive steroid levels in depression and these changes improve with antidepressant treatment. On the other hand, there are publications showing that BDNF and TNF-α and IL-1β levels are affected by rTMS treatment and this is associated with clinical improvement. In our study, it was aimed to evaluate the changes in neuroactive steroids (allopregnanolone, progesterone, DHEA, DHEA-SO4, estradiol, testosterone), BDNF, TNF-α and IL-1β levels, and their relationship with clinical response and cognitive functions, especially attention, with monotherapy rTMS treatment in MDD patients. . Method: 23 patients diagnosed with major depressive disorder according to DSM-5 criteria and 25 healthy controls who were similar to these patients in terms of age, gender and education level were included in the study. The participants were given a sociodemographic data form, Hamilton Depression Rating Scale (HDRS), Pittsburg Sleep Quality Index (PUKI), World Health Organization Disability Assessment Scale (WHO-DAS-2), Trail Making Test and Digit Span Tests for the evaluation of cognitive functions. In order to monitor the change in the depression levels and sleep quality of the patients, weekly measurements were made with HDRS and PUKI. WHO-DAS-2 and cognitive tests were performed before starting rTMS treatment and performed at the fourth and eighth weeks of treatment. In our study, biomarkers (allopregnanolone (ALLO), DHEA, progesterone, DHEA-S, estradiol, testosterone, BDNF, TNF-α and IL-1β) levels were studied in the peripheral blood taken from all patients before the rTMS treatment, at the end of the fourth week when rTMS treatment was applied 5 days a week, and at the end of the eighth week when the treatment was finished with the maintenance treatment applied once a week. For women, peripheral blood collection was performed at the follicular phase to provide baseline standardization as neuroactive steroids are affected by the menstrual cycle. Blood was drawn from all participants between 8.00 and 09.00 in the morning. In the control group, compliance with these criteria was achieved. Results: According to the results of our study, at the end of the fourth week of treatment, 6 (26%) of 23 patients were in remission because their HDRS score was below 7 points. In 15 of them (65%), the HRDS score decreased by 50%, that is, a response was observed. When the rTMS maintenance treatment was finished after the eighth week, it was seen that 16 patients (69.5%) had a HDRS score below 7 and reached remission. On the other hand, in 20 (87%) patients, the HDRS score decreased by 50% and they responded to the treatment. In addition to the increase in BDNF and allopregnanolone levels with monotherapy rTMS treatment, the decrease in TNF-α, IL-1ß, DHEA and DHEA-S levels was found to be statistically significant. The scores of the Trail Making test and the Digit Span test, which are give an idea about executive functions, especially attention, also changed positively with the treatment. In particular, a positive, moderately significant correlation was found between BDNF levels and the Number Range test both at the end of the fourth week and at the end of the eighth week. As a result of the comparison of serum BDNF levels of the patient and healthy control groups before rTMS treatment, it was found to be statistically significantly lower in the patient group. In addition, the increase in serum BDNF levels in the patient group with rTMS treatment was found to be significant both at the end of the fourth week (p<0.001) and the eighth week (p<0.001). However, both TNF-α and IL-1ß levels were statistically significantly decreased at the end of the eighth week (p<0.001). TNF-α level both decreased significantly at the end of the fourth week compared to the pre-treatment (p=0.023) and continued to decrease statistically significantly during the maintenance rTMS treatment period from the fourth to the eighth week (p=0.024). IL-1ß level decreased during the first four weeks of treatment, but it was not found statistically significant, but continued to decrease during the treatment period from the fourth to the eighth week, and the rate of decrease in this period was found to be statistically significant. Considering the change in the digit span test scores with rTMS treatment, it was seen that the rate of increase in the digit span test was statistically significant at the end of the 5 sessions of 4 weeks rTMS treatment before the treatment and at the end of the first month (p<0.001). When the scores at the end of the first month and at the end of the second month were compared, no statistically significant result was reached here (p<0.001). Considering the relationship between the change in Trail Making tests and rTMS treatment, there was no statistically significant difference between the pretreatment and the end of the first month and the end of the first and second months for the trailing A test (p = 0.484). However, when the pre-treatment and the end of the treatment, that is, the end of the second month, were compared, there was a statistically significant difference (p = 0.009). There was a significant difference in error status for the trailing A test (p = 0.012). For the trailing B test, both the values before the treatment and at the end of the fourth week, and the values between the fourth week and the eighth week were found to be statistically different (p<0.001). A significant relationship was also observed for the change in the number of errors (p= 0.027). Conclusion: In our study, rTMS was found to be effective in MDD patients. This effect can be related to the neuroendocrine effect by connecting to the change in neuroactive steroids. In addition, the statistical increase in serum BDNF level with rTMS treatment also supports the neurotrophin hypothesis. On the other hand, the change in TNF-α and IL1β levels can be interpreted as an immunological change contributing to the existing antidepressant effect. However, it can be said that associating the changes in existing biomarkers with cognitive functions, rTMS can be effective on cognitive functions, and it can be said that conducting similar studies with cognitive scales that measure in a wider area will contribute to the clarification of this issue. Keywords: BDNF, Cognitive Functions, IL-1ß, Neuroactive Steroids, rTMS, TNF- α